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(2013)Parkinson's disease is a neurodegenerative disease which is characterized by progressive loss of dopaminergic neurons in the substantia nigra and formation of intracellular Lewy bodies. α-synuclein is an essential part of Lewy bodies. In addition, mutations in the α-synuclein gene have been found to cause rare familial forms of Parkinson's disease. Animal models of Parkinson's disease are created by neurotoxins, transgenic animals and viral vectors. Transgenic animal models and viral vector models seem to reflect the pathology of Parkinson's disease better than the traditional neurotoxin models. In the transgenic animal models, the transgene and the promoter used in the expression of the transgene guide the pathology and motor dysfunctions that the animal model exhibits. In the viral vector models, it is important to use a suitable animal strain and a correct viral serotype in order to express the transgene sufficiently enough in the laboratory animals. The aim of the study was to investigate the ability of adeno-associated viral vector (AAV1-vector) to transfect WT- or A53T-α-synuclein gene into the striatum or the substantia nigra, and the effects of their overexpression on motor functions and concentrations of striatal dopamine and its metabolites in mice. In addition, the effect of a prolyl endopeptidase (PREP) inhibitor on the overexpression of A53T-α-synuclein in the mouse nigrostriatal pathway was studied, as PREP has been found to stimulate the aggregation of α-synuclein and therefore perhaps to increase neurotoxicity of α-synuclein. There were no statistically significant differences between the groups in the motor function tests (locomotor activity, rotarod and balance beam walk). Green fluorescent protein immunostaining showed that the GFP gene was weakly transfected into the striatum by the AAV1-vector, and no overexpression was observed. There were only minor differences in the striatal concentrations of dopamine and its metabolites. Finally, PREP-activity measurements showed that PREP-inhibitor (KYP-2047) treatment had poorly reduced PREP-activity. In this study, the viral vectors did not induce the overexpression of α-synuclein, although previously AAV2- and AAV6-vectors have been efficient in mice and rats. High PREP-activities that were found in most of the samples probably resulted from failed installations of mini-pumps that delivered the PREP-inhibitor. While in this study the viral vectors were not a successful attempt in the creation of an animal model of Parkinson's disease, they are an important method to model Parkinson's disease in the future.
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(2017)lcohol addiction is a significant public health problem worldwide, and its treatment is extremely challenging. One major problem in the treatment of alcohol addiction are the later relapses to uncontrollable drinking. Approximately 60-70 % of addicts relapse to drinking within a year from the beginning of the treatment. The current treatment of alcohol addiction is based on a combined psychotheraphy and pharmacological treatments, but even at the best the efficacy remains quite modest. This is why further studies on the underlying mechanisms behind alcohol addiction and development of more effective pharmaceuticals to treat it are an important field of research. Chronic exposure to the rewarding effects of alcohol causes neurochemical adaptations in the brain reward system. These adaptations strive to restrain the recurring rewarding signals caused by alcohol and lead eventually to increased reward thresholds in the reward system. As the reward thresholds increase, the individual develops tolerance to the rewarding effects of alcohol, but also craving for the substance and a dysphoric mental state which are highlighted especially during periods of abstinence. It is known that the increase in reward thresholds is an important factor leading to relapses, but the exact nature of the neurochemical adaptations behind it are not known. According to recent studies dynorphin -peptides (DYN) and κ-opioid receptors (KOR) of the endogenous opioid system seem to have an important role in these neurochemical adaptations. It has been shown that chronic alcohol exposure increases the activity of DYN/ KOR -system especially within the nucleus accumbens (NAc), which is an essential structure of the brain reward system. The increased activity of the DYN/ KOR -system in the NAc has been shown to inhibit the development of rewarding signals. Previous studies have shown that inhibiting the increased activity of the DYN/ KOR -system with a selective KOR-antagonist, reduces voluntary alcohol intake and relapse-like alcohol seeking behavior during periods of abstinence, especially in physically addicted animals. In this study we studied the relapse-like alcohol drinking of Long-Evans rats in the alcohol deprivation effect (ADE) model. The effects of selective and long-acting KOR-antagonists, JDTic and nor-BNI, were tested on the ADE-effect which occurs after a period of deprivation. The ADE is defined as a transient increase in alcohol intake after a forced period of abstinence and it has been shown both in rodents with a history of alcohol consumption, and human alcohol addicts. In this study the rats were allowed to consume alcohol (10% ethanol-water solution) voluntarily during 90 minutes for 10 consecutive days after which followed a six days long deprivation period. According to results, both intra-accumbally (15 µg/ 0,3 µl/min/ site) or subcutaneously (10 mg/kg) administered JDTic decreased the ADEeffect significantly compared to vehicle, when administered 24 hours prior the end of the deprivation period. Also intra-accumbally administered nor-BNI (3 µg/0,3 µl/min/site) decreased the ADE-effect significantly compared to vehicle when administered 24 hour prior the end of deprivation. The results are in line with the theory that alcohol induces sensitization of the DYN/ KOR -system within the brain structures involved in reward. In theory it can be speculated that by suppressing the activity of the DYN/ KOR -system, KOR-antagonists can relieve craving for alcohol. This can be seen as a decrease in relapse-like consumption of alcohol. In conclusion, it can be suggested that by suppressing the increased activity of the DYN/ KOR -system induced by chronic alcohol exposure with a selective KOR-antagonist, like JDTic or nor-BNI, it could be possible to reduce the risk of relapse during abstinence and thus improve the efficacy of treatments for alcohol addiction.
Now showing items 625-626 of 626